The role of the brain endothelium in neuroinflammatory responses to social stress

点击翻译按钮获取中文摘要

PROJECT SUMMARY / ABSTRACT Inflammatory signaling after psychosocial stress may mediate maladaptive physiologic and behavioral responses to stress. For example, patients with anxiety or depression often have increased pro-inflammatory cytokines in circulation and altered leukocyte function, which correlates with disease severity and resistance to treatment. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates key components of the human response to chronic social stress, including increased circulating cytokines, production of pro-inflammatory monocytes, and development of anxiety-like behaviors. We have previously shown that RSD alters bidirectional signaling between the brain and immune system specifically in regions of the brain associated with threat appraisal and behavioral responses to stress, such as the amygdala and prelimbic cortex. Within these regions, microglia become activated, and recruit circulating pro-inflammatory monocytes to neurovascular endothelial cells. Monocyte signaling to endothelial cells through the interleukin(IL)-1β receptor (IL-1R1) is critical for the development of anxiety-like behavior after stress. Currently, the endothelial response to monocyte-derived IL-1β is unknown. Here, I show preliminary data that IL-1β may decrease endothelial tight junction protein expression and induce cyclooxegenase-2, an enzyme involved in prostaglandin production. This proposal will investigate how neurovascular endothelial function changes after stress by addressing whether inflammatory signaling impacts the permeability of the blood-brain barrier and revealing whether endothelial-derived prostaglandins impact other cells of the central nervous system (CNS). I propose three aims to test the hypothesis that IL-1β signaling through endothelial IL-1R1 disrupts tight junction integrity in regions involved in fear and threat appraisal, and stimulates endothelial production of prostaglandins which signal to CNS cells to impact behavioral responses to stress. First, I will determine whether RSD decreases tight junction protein expression in IL-1R1+ endothelial cells and if RSD increases blood-brain barrier permeability. Next, I will characterize the transcriptional profile of neurovascular endothelial cells within fear-responsive regions of the brain after RSD with and without the IL-1β signal from monocytes. Finally, I will inhibit prostaglandin production using pharmacologic interventions and genetic knockouts to elucidate the effects of endothelial-derived prostaglandins on neuronal and microglial activation and behavioral deficits after RSD. Overall, this will reveal a novel mechanism by which stress can perturb immune signaling in the CNS which ultimately impacts behavior. Understanding the biology of stress responses is vital to understanding mental health disorders, which are highly prevalent in the population. Neurovascular endothelial cells are a potential target for therapeutic intervention to prevent and treat disorders such as anxiety and depression.